CA2823767A1 - Abnormal cannabidiols as agents for lowering intraocular pressure - Google Patents

Abnormal cannabidiols as agents for lowering intraocular pressure Download PDF

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CA2823767A1
CA2823767A1 CA2823767A CA2823767A CA2823767A1 CA 2823767 A1 CA2823767 A1 CA 2823767A1 CA 2823767 A CA2823767 A CA 2823767A CA 2823767 A CA2823767 A CA 2823767A CA 2823767 A1 CA2823767 A1 CA 2823767A1
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compound
group
alkyl
methyl
hydrogen
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June Chen
Hans Fliri
Simon Pettit
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Allergan Inc
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Allergan Inc
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Priority claimed from US11/409,570 external-priority patent/US7612101B2/en
Priority claimed from US11/409,868 external-priority patent/US7718830B2/en
Priority claimed from US11/409,871 external-priority patent/US7618966B2/en
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of CA2823767A1 publication Critical patent/CA2823767A1/en
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract

The present invention provides a method of treating glaucoma or ocular hypertension which comprises applying to the eye of a person in need thereof an amount sufficient to treat glaucoma or ocular hypertension of a compound of formula (I), wherein Y, Q, Z, R, R1 and R2 are as defined in the specification. The present invention further comprises pharmaceutical compositions, e.g. ophthalmic compositions, including said compound.

Description

, 17909ABC(AP) ABNORMAL CANNABIDIOLS AS AGENTS FOR LOWERING
INT'RAOCULAR PRESSURE
BACKGROUND OF [HE INVENTION
1. Field of the Invention The present invention relates to the use of Abnormal Cannabidiols to lower the intraocular pressure of mammals and thus are useful in treating glaucoma.
2. Background of the Related Art Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow.
In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impede& In acute or chronic angle-closure, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm Dilation of the pupil may push the root of the iris forward agRinst the angle, and may produce pupilary block and thus precipitate an acute attack Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical a-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Certain Abnormal Cannabidiols are disclosed in Howlett et al, "International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors", Pharmacological Reviews 54: 161-202, 2002.
Reference is made to Published -U.S. Patent Application Numbers 2005/0282902, 2005/0282912 and 2005/0282913 to Chen et al which were published on December 22, 2005 (June Chen is a co-inventor of each of said published patent applications and the present patent application.) Summary of the Invention We have found that Abnormal Cannabidiols are potent ocular hypotensive agents. We have further found that Abnormal Cannabidiols and homologues and derivatives thereof, are especially useful in the treatment of glaucoma and surprisingly, cause no or significantly lower ocular surface hyperemia than the other compounds that are useful in lowering intraocular pressure. e.g. PGF2a and lower alkyl esters thereof.
The present invention relates to methods of treating ocular hypertension which comprises administering an effective amount of a compound represented by y1 wherein Y is selected from the group consisting of keto and hydroxyl;
Y1 is selected from the group consisting of hydroxyl, keto, halogen and C1-05 alkyl;
Z is N or C;
Q is selected from the group consisting of phenyl, halogen-substituted phenyl, or 6 member heterocyclic radicals, wherein the hetero atom is nitrogen, oxygen or sulfur, ,Z\
R4 'R8 wherein W is a direct bond or C(R11)(R12);
a dotted line represents the presence or absence of a double bond;
the wavy line represents a direct bond;
Q and Y may form a condensed ring wherein Y is ¨C(0)-NR3- and Q is ¨
C(Q')- wherein Q' is R3 or said C is a spiro atom and Q', together with said C, represents a carbocyclic or heterocyclic ring having from 3 to 6 carbon atoms and said hetero atom is N, 0 or S;
R is selected from the group consisting of H, halogen and Cl..5 alkyl;
R1 is selected from the group consisting of H and halogen;
R2 is selected from the group consisting of H, Ci..5 alkyl, halogen, XC 1-5 alkyl, C 1.5 allcylOR13, C1_5 alkylN( R13 )2, N( R13 )2, XC 1.5 alkylN( R13 )2 and XC 1.5 allcylOR13; wherein Xis 0 or S( 0 )n;
n is () or an integer of from 1 to 2;
R3 is selected from the group consisting of H, hydroxyl, oxo, C1_5 alkyl, C1-5 alkylOR13 and C1_5 alkylN( R13 )2;
R4 is selected from the group consisting of H, C1.5 alkenyl, C1.5 alkyl, C1-5 alkylOR13 and C1_5 alkylN( R13 )2;
R5, R6, R7, Rs, Rs,R10,Rn, R12 are independently selected from the group consisting of H, C1-5 alkyl, C1_5 alkylOR13 and OR and and R13 is selected from the group consisting of H, C1_5 alkyl and C3-8 cyclic alkyl, or two R13 groups, together with N, may form a cyclic ring such as a piperidine or morpholine ring; and provided that R8 and R12 may, together, form a cyclic ring, and R3 and R5 may, together, represent 0, and when Q is menthadiene, R1 and R2 are H and Y is hydroxyl, R may not be H or alkyL
Preferably, the compound of formula I is zI

y 1 wherein Y is selected from the group consisting of keto and hydroxyl;
Z is N or C;
Q is selected from the group consisting of ,Zµ
R4 'Rs wherein W is a direct bond or C(R11)(R12);
a dotted line represents the presence or absence of a double bond;
wherein R is selected from the group consisting of H, halogen, e.g. bromo or chloro; and C1-5 alkyl; RI is selected from the group consisting of H, halogen, e.g. bromo or chloro;
R2 is independently selected from the group consisting of H, C1-5 alkyl, halogen, XC 1.5 alkyl, C 1-5 allCY1OR13, C1-5 alkyIN( R13 )2, N( R13 )2, XC ancylN( R13 )2 and XC 1.5 alkylOR13;
Xis 0 or S( 0 )fl;
n is 0 or an integer of from 1 to 2;
R3 is selected from the group consisting of H, hydroxyl, C1.5 alkyl, C1-5 alkylOR13 and 01.5 alkyN( R13 )2;
R4 is selected from the group consisting of H, C1_5 alkenyl, e.g. isopropenyl, C1.5 alkyl, Ci.5 alkyl OR13 and C1.5 alkylN( R13 )2;
R55 R65 R75 Rs, R95 Rio, ¨115 K R12 are independently selected from the group consisting of H, Ci_5 alkyl, C1.5 alkylOR13 and OR'; and R13 is selected from the group consisting of H, 01.5 alkyl and C3_8 cyclic alkyl, or two R13 groups, together with N, may form a cyclic ring such as a piperidine or morpholine ring; and provided that any of said alkyl groups may be substituted with a hetero atom containing radical, wherein said heteroatom is and R12 may, together, form a cyclic ring;
and R3 and R5 may, together, represent 0, and when Q is menthadiene, R1 and R2 are H and Y is hydroxyl, R may not be H or alkyl.
In a further aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulae (I) or (r), in admixture with an non-toxic, pharmaceutically acceptable liquid vehicle. Such pharmaceutical compositions may be ophthalmic solutions which are useful in treating ocular hyptension and/or glaucoma. Finally, the present invention provides certain novel compounds which are useful in treating ocular hypertension and/or glaucoma.
Brief Description of the Fieures Figure 1 shows the effect of abnormal cannabidiol on intraocular pressure.
Figure 2 shows the effect of the compound of Example 4 intraocular pressure.
Figure 3 shows the effect of the compound of Example 3 intraocular pressure.
Figure 4 shows the effect of the compound of Example 6 intraocular pressure.
Figure 5 shows the effect of the compound of Example 5 intraocular pressure.
Detailed Description of the Invention The present invention relates to the use of Abnormal Cannabidiols as ocular hypotensives. These therapeutic agents are represented by compounds having the formula I or I', above.
In one embodiment of the invention, the compound is selected from the group consisting of abnormal Cannabidiols and analogues thereof represented by formula II

HO OH
wherein Q is selected from the group consisting of Ri R7 111101 and 111) A particularly preferred group represented by Q is menthadiene or In this class of compounds, preferably, R is selected from the group consisting of hydrogen, methyl, bromo and chloro and Rl is selected from the group consisting of hydrogen, methyl and chloro.
Compounds of this type may be prepared by condensation of a cyclic alkene or cyclic alcohol with a suitably substituted benzene-1,3-diol. The reaction is catalysed by an acid such as oxalic acid ciihydrate or p-toluenesulphonic acid.
The reaction is carried out in a solvent or mixture of solvents such as toluene, diethyl ether or dichloromethane. A mixture of the two isomers is obtained and the desired product is separated by chromatography. The reaction scheme is illustrated below.
6:IH OH
oR HO2CCO2RH2.
110 R li +
+
toiuene a HO OH lip io R
ether 7 HO OH \ Ho 41111 + R5 R R1 R5 R11 R6 R1 HO,CCO2H. 2H20 R11 -- R6 I
R10=

R7 . ,-õ_, bluene R10 el R7R

Lin HO ether R9 =RE I

The synthesis of the starting materials is well known.
The mechanism of the reaction is the result of the formation of a carbocation by elimination of OH or a starting material containing a functional group such as acetate which can also be eliminated to give the carbocation can be used.
OH
111111 __________ =
40 +

_________________ =
Cl.'..OH
In another embodiment of the invention the compound is tetrahydropyridine represented by formula III
Ri HO OH

111.
These tetrahydropyridine compounds may be synthesized according to the following reaction scheme wherein Me is methyl, Bu is butyl and iPr is isopropyl.
Br OMe BuLi / Ether NaB H4 0 Me0H
OMe ( 1 ) N+I (6) R4= Me r (7) R4= ipr (4) R4= Me (2) R4= Me (5) R4 = 'Pr (3) R4 =IPr BE3r3 '`=-= OH
CH2Cl2 OH
(6) R4= Me (9) R4= 'Pr In a further embodiment of the invention, the compound is a piperidinedione represented by the formula IV
R

N -/
0 OH n7.
These compounds may be synthesized according to the following reaction scheme wherein Et is ethyl, TI-LF is tetrahyclrofuran and DMiF is dimethyl formamide.

,,,/R1 el .4- HN NaH
______________________________________ . R
I. )R1 L 00Et THF or DMF N
R4 R4 ,..,/,,,,,, 0 OEt or D D. R3 i 1-µ11 le 1 N8 R1s R7 401 R,,,,, 71 L

or R12 R5, .10 ISO R7 Rg Rs 40 CH
Where L is a leaving group such bromine, iodine or tosyl.
Compounds of formula F wherein Y and Y1 are keto are known as piperidine-2, 4-diones and may be synthesized as described by EL Nishino, et al., Teterahedron 2005, 11107-11124. The corresponding cyclohexane-1, 3 diones may be prepared as described in EP 291114 and EP 310186.
Compounds of formula I' wherein Y is keto and Y1 is hydroxyl are known as 4-hydroxypyridin-2-ones and may be prepared as described by Castillo, et al. in Bull. Soc. Chim. Fr. 1982, 257-261.
The compounds wherein Y=Y1=hydroxyl may be prepared by dehydrogenation of the corresponding cyclohexane ¨1, 3 diones by the method described by ED. Berymann, et a., JACS, 1953, 3226. Compounds of formula wherein both of Z is N, Y is oxo and Y1 is hydroxyl may be prepared as described in WO 2005/007632 and J. Het. Chem. 1989, 169-176.
In all of the above formulae, as well as in those provided hereinafter, the straight lines represent bonds. Where there is no symbol for the atoms between the bonds, the appropriate carbon-containing radical is to be inferred.
Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to thc present invention, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0%
(w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, = benz-alkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Twe,en 80.
Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisnlfite, sodium thiosulfate, acetylcysteine, butyiated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
The ingredients are usually used in the following amounts;
Ingredient Amount ("Ye w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make 100%
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
One package may contain one or more unit doses.
Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five unit doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 41.
The compounds disclosed herein for use in the method of this invention, i.e. the treatment of glaucoma or elevated intraocular pressure, may also be used in combination with other drugs useful for the treatment of glaucoma or elevated intraocular pressure.
For the treatment of glaucoma or elevated intraocular pressure, combination treatment with the following classes of drugs are contemplated:
13-Blockers (or 13-adrenerp-ic antagonists) including carteolol, levobunolol, metipranolol, timolol hemihydrate, timolol maleate, 131-selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Adrenergic Agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof; and az-selective adrenergic agonists such as apraclonidine, brimonichne, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Carbonic Anhvdrase Inhibitors including acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Cholinergic Agonists including direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
chlolinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Glutamate Antagonists such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, ciiphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, lidoflazine, prenylamine lactate, amiloride, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and Prostaglandins including travoprost, UFO-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like.
The invention is further illustrated by the following non-limiting Examples.
Example 1 Intraocular Pressure Intraocular pressure was measured by applanation pneurnatonometry in conscious animals. The test compound was administered topically to one eye while vehicle was given to the fellow eye in a masked fashion. Ocular normotensive Beagle dogs (males, females) were dosed once daily for five days. Laser-induced unilaterally ocular hypertensive Cynomolgus monkeys (females) were dosed once daily for 4 days. Student's paired t-test was used for statistical comparisons. Differences were considered statistically significant if the P-value is less than 0.05.
The results are shown in the Figures.
The figures show the change from baseline IOP of Monkey dosed with 0.1% of the active compound versus time.
Example 2 Determination of Abnormal Cannabidiol Activity Abnormal Cannabidiol receptor activity may be measured in accordance with the procedure disclosed in (Wagner JA et al., Hypertension 33 [part Ifj, (1999); Jarai Z et al., PNAS 96, 14136 (1999) .
Experimental Details for Synthesis of Abnormal Cannabidiols General Route OH OH
R HO,CCO,H.H20 Ito los HO OH toluene i I 7 ether HO OH 7 HO R
Example 3 5-methyl-4-(6-Isoprenyl-3-methyleyelohex-2-enyObenzene-1,3-diol (4R)-1-Methy1-4-isoprenylcyclohex-2-ene-1 -ol ( 300mg, 2mmoles ) was dissolved in toluene ( 20m1) and 5-methylresoreinol ( 248mg, 2mmoles ) was added in diethyl ether ( 5m1 ). Oxalic acid dihydrate ( 252mg, 2mmoles ) was added and the reaction mixture heated with stirring at 80 for 5 hours. The reaction mixture was allowed to cool and diluted with diethyl ether ( 30m1).
The ether solution was washed twice with aqueous sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure to give the crude product as a brown oil ( 800mg ). The product was purified using a silica column eluted with ethyl acetate:
isohexane 1: 9 going to ethyl acetate: isohexane 2 : 8.
The product was isolated as a yellow gum ( 106mg ) Example 4 4-(6-lsopreny1-3-methylcydohex-2-enyl)benzene-1,3-diol The named compound is prepared according to the method described in Example 3 except that resorcinol is substituted for 5-methylresorcinol.
NMR ( 300MHz, CDCI3 ) 6.2 ( M, 2H), 6.1 ( S, 1H), 5.55 ( M, 1H), 4.7 ( M, IH ), 4.55 ( S, 1H ), 4.5 ( M, 1H), 3.55 ( M, 1H), 2.5 ( M, 1H ), 2.2 ( M, ), 2.15 (S,3H),1.85 (M, 2H), 1.8 (S,3H), 1.6 (S,3H) Also prepared in a similar manner were Example 5 5-Chloro-4-( 6-Isopreny1-3-methyleyclohex-2-enyl )benzene-1,3-cliol NMR ( 300MHz, CDCI3 ) 6.4 ( M, 1H), 6.3 ( M, 1H), 6.25 ( S, 1H), 5.6 ( M, 1H), 4.7 (brS, 1H), 4.65 (M, IH), 4.4 (A, 1H), 4.0 (M, 1H), 2.5 (M, 1H),2.25 (M,1H),2.15 (M, 1H),1.85 (M, 2H),I.8 (S,3H),1.6(S,3H) Example 6 4-( 6-1.soprenyl-3-methylcyclohex-2-enyl )-5-methoxybenzene-1,3-diol 'H NI. ( 300MHz., CDC13 ) 6.15 ( brS, 1H), 6.0 ( M, 2H), 5.6 ( M, 1H), 4.65 ( brS, 1H), 4.5 (M, 1H ), 4.35 (M, 1H), 3.95 ( M, 1H), 3.7 ( S, 3H ), 2.4 ( M, 1H), 2.25 ( 1H, M), 2.1 ( M, 1H), 1.8 ( M, 2H), 1.8 ( 5, 3H), 1.65 ( S, 3H) Example 7 2-( 6-lsoprenyl-3-methyleyelohex-2-enyl )-5-methoxybenzene-1,3-diol 1H NMR ( 300MHz, ODD;) 6.0 ( brS, 2H), 5.55 ( M, 1H), 4.7 ( M, 1H), 4.6 ( M., 1H), 3.8 ( M, 1H), 3.75 ( S, 3H), 2.4 (M., 1H), 2.2 ( M, 1H), 2.1 (M,1H),1.8(S,3H),1.8(M,2H) Example 8 Synthesis of 6-Chloro-4-( 6-Isopreny1-3-methylcyclohex-2-enyl)benzene-1,3-diol 4-Chlororesorcinol ( 350mg, 2.4mmoles ) was dissolved in toluene ( 30m1) and diethyl ether ( 20m1) and p-toluenesulphonic acid ( 91mg, 0.48mmoles ) was added.
(4R)-1-Methyl-4-isoprenylcyclohex-2-ene-1-ol ( 500mg, 3mmoles ) in toluene ( lOral ) was added and the reaction mixture was stirred at room temperature for 6 hours. Diluted with diethyl ether ( 30m1) and washed twice with aqueous sodium bicarbonate. Dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give a yellow gum ( 800mg ).
Purified using a silica column eluted with ethyl acetate: isobexane 9:1 going to ethyl acetate : isohexane 8:2. The product was isolated as a yellow gum ( 95mg 1H NMR ( 300MHz, cDa3 ) 6.9 ( S, 1H), 6.5 ( S, 1H), 5.5 ( S, 1H), 5.45 ( M-, 1H), 5.35 ( S, 1H), 4.7 ( M. 1H), 4.6 ( M, 1H), 3.35 ( M, 1H), 2.2 ( M, 3M), 1.8 ( M, 3H ), 1.75 ( M, 2H ), 1.6 ( S, 3H ) Example 9 Synthesis of 4-Cycloherylbenzene4,3-diol This compound was prepared as described in JACS, 1953, 2341.
Resorcinol (2.2g. 0.02 moles ) was mixed with cyclohexanol ( lg, 0.01moles ) and zinc (II) chloride ( 0.48g, 0.0035moles ) and the reaction mixture heated to 150 with stirring. After heating 2 hours, the reaction mixture was allowed to cool and then dissolved in ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated to give a brown oil ( 3.0g ). Excess resorcinol was evaporated by heating in a Kugelrohr oven under reduced pressure (2000, 2mmHg ). Purified using a silica column eluted with ethyl acetate: isohexane 2:8 to give the product as a yellow oil ( 0.5g ).
Trituration with isohexane gave the product as a white solid ( 0.2g ).
11-1NMR ( 300MHz, CDCI3) 7.0 ( D, 1H J= 8Hz ), 6.4 ( M, 1H ), 6.3 (M, 1H
),4.7(S,IH),4.55(S,1H),2.7(M,1H),1.8(M,5H),1.4(M,5H) Example 10 Synthesis of 4R-Isopreny1-1-methylcyclohex-2-enol The synthesis of 4R-Isopreny1-1-methylcyclohex-2-enol was carried out as described in W02004096740.
OH õr-,o Morph line OH 0 1-4,02 LiCI Et0H 0 Et0H
Silica toluene OH
Example 11 4-lsopreny1-1-methyl-2-morpholin-4-yl-eyelohexanol ( + )-Limonene oxide ( 13.2g, 0.087moles ) was dissolved in ethanol ( 40m1 ) and lithium chloride ( 5.9g, 0.14moles ) was added with stirring. Morph line ( 11.4g, 0.13moles ) was added and the reaction mixture was heated at 600 for 48ho-urs. The solvent was evaporated under reduced pressure and the residue taken up in dichloromethane. Washed with water. Extracted into 2M
hydrochloric acid and washed with dichloromethane. Basified to pH 10 by addition of 2M sodium hydroxide. Extracted with diethyl ether and washed with water. Dried over an_hydrous magnesium sulphate and evaporated the solvent under reduced pressure to give the product as a yellow oil ( 10.3g ) 1H NMR ( 300MHz, CDC13 ) 4.95 ( M, IH ), 4.85 ( M, 1H), 3.7 ( M, 4H), 2.75 ( M, 2H), 2.5 ( M., 4H), 2.1 ( M, 1H), 1.95 ( M, 1H ), 1.75 ( S, 3H), 1.6 ( M, 4H), 1.2 (S,3H) Example 12 4-Isoprenyl-1-methyl-24 4-oxy-rnorpholin-4-y1)-cyclohexanol 4-1sopreny1-1-methyl-2-morpho1in4-y1-cyclohexanol ( 17.7g, 0.074 moles) was dissolved in ethanol ( 100ml ) and 35% hydrogen peroxide ( 37m1, 0.325moles ) was added. Heated with stirring at 500 for 6 hours. 5% palladium on carbon ( 100mg ) was added in order to decompose the excess peroxide.
Stirred at room temperature for 3 hours. ( Peroxide test papers gave a negative result) Filtered through a pad of HiFlo to remove the palladium on carbon and the solvent was evaporated under reduced pressure to give the product as a yellow oil ( 22.2g ).
1HNMR ( 300MHz, CDCI3 ) 5.5 ( M, 1H), 4.85 ( M., 1H), 4.5 ( M, 2H), 3.7 ( M., 4H ), 3.4 ( M, 3H), 2.95 ( M, 1H), 2.65 ( M, 1H ), 2.25 ( M, 1H ), 2-0 ( 1H), 1.85 ( M, IH ), 1.75 ( M, 1H), 1.75 ( S, 3H), 1.55 (lvi, 1H), 1.55 ( S, 3H) Example 13 4R-Isopreny1-1-methyleyclohex-2-enol 4-Isopreny1-1-methy1-2-morpholin-4-yl-cyclohexanol ( 4.6g, 0.018 moles ) was dissolved in toluene ( 80m1) and silica ( Lig ) was added. The reaction mixture was heated to reflux with stirring. Water generated in the reaction was removed using Dean and Stark apparatus. After refluxing overnight, the silica was removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil ( 4.0g ). Dissolved in dichloromethane and washed with 2M hydrochloric acid.
Washed with water and dried over anhydrous magnesium sulphate. The solvent was removed by evaporation under reduced pressure to give the product as a brown oil ( 1.3g ).
11-1NMR ( 300MHz, CD03 ) 5.7 ( M., 2H ), 4.8 ( M, 2H ), 2.7 ( M, 11-1), 1.8 ( M, 2H ), 1.75 ( S, 3H), 1.65 ( M, 2H ), 1.3 ( S, 3H) Experimental details for Synthesis of Tetrahydropyridines =

=me BuLi / Ether NaBH, =.õ, 0 OMe Me0H ____________________________________ 7 I

(1) I I- (6) R = Me (4) R = Me (5) R = (7) R =
(2) R = Me (3) R = Pr BBrs ..`N OH
CH2Cls R
= H
(6) R= Me (9) R = Pr Scheme Example 14 Preparation of 2-(2,4-Dimethoxypheny1)4,4-dimethy1-1,2-dihydropyridine.
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5g, 2.3mmol) in diethyl ether (10m1) cooled at -78 C under nitrogen was added a solution of n-butyl lithium (1.0m1, 2.5mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at -78 C for 2 hours and then 1,4-dimethyl pyridinium iodide (2) (0.54g, 2.5=01) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20m1) and extracted with diethyl ether (2 x 15m1). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxypheny1)-1,4-dimethy1-1,2-dihydropyridine (4) (0.5g, 93%) as a brown oil, 1H NMR

-2c-CDC13 ??1.7 (s, 3H), 2.7 (s, 3H), 3.8(s, 6H), 4.45 (dd, 1H, J= 2,7) 4.85 (m, 1H), 5.4 (d, 1H, J= 4), 6.05 (d, 1H, J= 7), 6.45 (d, 1H, J= 3), 6.55 (m, 11-1), 7.5 (d, 1H, J= 9).
By proceeding in a similar manner starting from 2,4-dimethoxybromobenzene (1) and 1- isopropyl-4-methyl pyridinium iodide (3), 2-(2,4-dinnethoxypheny1)-1-isopropyl-4-methyl-1,2-dihydropyidine (5) was prepared, 1H NMR CDCI3 ?
(d, 6H J= 7), 1.7 (s, 3H), 3.15 (m, 1H), 3.7 (s, 6H), 4.5 (d, 1H J= 8), 4.8 (m,1H), 5.5(5, IH J= 5), 6.3 (d, 1H J= 7), 6.45 (d, 1H J= 2), 6.55 (m, 1H), 7.55 (d, IH J= 8).
Example 15 Preparation of 6-(2,4-Dimethoxypheny1)-1,4-dimethyl-1,2,3,6-tetrabydro-pyridine (6).
To a stirred solution of 2-(2,4-dimethoxypheny1)-1,4-dimethy1-1,2-dihydropyridine(4) (0.48g, 2.06mmol) in methanol (5m1) at room temperature was added sodium borohydride (98mg, 2.51mmol), gas evolution commenced immediately, the resulting mixture was stirred for 3 hours. At this time the solvent was evaporated and the residue suspended in water (5m1) and extracted with ethyl acetate (2 x 10m1). The organic extract was then extracted with 2M
hydrochloric acid (2 x 15m1). The aqueous layer was basified with 2M sodium hydroxide and extracted with ethyl acetate (2 x 20m1), the organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated to yield 6-(2, 4-dimethoxypheny1)-1,4-dimethy1-1,2,3 , 6 -tetrahydropyri din e (6) (350mg, 73%) as a yellow oil, 1H NMR CDC13 8?1.55 (s, 3H), 1.9 (in, 1H), 2.2 (s, 3H), 2.5(m, 2H), 2.95 (m, 1H), 3.8 (s, 6H), 4.1 (m, 1H), 5.2 (in, 1H), 6.5 (in, 2H), 7.3 (d, 1H J ---- 4).
By proceeding in a similar manner starting from 2-(2,4-dimethoxypheny1)-1-isopropy14-methyl-1,2-dihydropyidine (5), 6-(2,4-dimethoxyphenyI)-1-isopropy1-4-methy1-1,2,3,6-tetrahydropyridine (7) was prepared, 1H NMR
CDC13 5 0.95 (d, 3H J= 6), 1.05 (d. 3H J = 6), 1.7 (s, 3H), 1.9 (in, 1H), 2.5 (in.
1H), 2.85 (na, 1H). 3.0 (m,1H), 3.8 (s, 6H), 4.6 (s, 1H), 5.2 (s, 1 H), 6.45 (d, 1H
J= 3), 6.5 (dd. 1H J=3.8), 7.4 (d, 1H J= 8).
Example 16 Preparation 4-(1,4-Dimethy1-1,2,5,6-tetrahydropyridin-2-y1)-benzene-1,3-diol (8) To a stirred solution of 6-(2,4-dimethoxypheny1)-1,4-dimethy1-1,2,3,6-tetrahydro-pyridine (6) (300mg, 1.27mmol) in dichloromethane (20m1) cooled at 0 C under nitrogen was added boron tribromide (3.1m1, 3.18mmol of 1.0M
solution in dichloromethane), the resultant dark solution was allowed to warm to room temperature and stirred for 1 hour. The solution was poured onto ice and basified with sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (20m1), the combined organic layers were dried over anhydrous magnesium sulphate, filtered and evaporated to a gum (200mg). The material was purified on a lOg silica cartridge eluting with methanol/dichloromethanelammonia (7:92:1) to yield 4-m ethy I-1,2,5 ,6-tetrahy dropyri din-2 -y1)-b enzen e- 1 .3-diol (8) (93 mg, 35%) as a gum, 1H NMR D6-acetone ??1.67 (s, 311), 1.97 (m,1H), 2.3 (s, 311), 2.42 (m, 1H), 2.74 (m, 1H), 3.08 (in, 1H), 3.74 (s, 111), 5.15 (s, 1H), 6.2 (d, 1H
J= 2), 6.27 (dd, 1H J=2,8), 6.82 (d, 1H J= 8), 9.4 (bs, 2H).
By proceeding in a similar manner starting from 6-(2,4-dimetboxypheny1)-1-isopropy1-4-methyl- 1,2,3 , 6-tetrahydropyri dine (7), 4-(1-isopropy1-4--m ethyl-1,2,5,6-tetra-hydropyridin-2-y1)-benzene-1,3-diol (9) was prepared, NMR D6-acetone 60.81 (d, 3H .1= 7), 0.98 (d, 3H J= 7), 1.52 (s, 3H), 1.84 (m, 1H), 2.15(m, 1H), 2.29(m, 1H), 2.94 (m, 2H), 4.09 (s, 11.1), 4.97 (s, 1H), 6.05 (d, J= 3), 6.11(dd, J= 3,8), 6.68 (d, J= 8), 9.6 (bs, 2H).

&ample 17 Preparation of 1- Isopropyl-4-methyl pyridinium iodide (3).
To a stirred solution of 4-picoline (2.5g, 26.8mmol) in acetonitrile (50m1) was added isopropyl iodide (9.1g, 53.6mmol) drop wise, the resultant mixture was heated at 90 C for 24 hours. After cooling the solvent was evaporated to give a red solid which on trituration with ethyl acetate yielded 1- isopropyl-4-methyl pyridiniurn iodide (6.01g, 85%) as a cream solid, Ili NMR D6-DMS0 8?1.6 ( d, 6H, J= 7), 2.6 (s, 3H), 4.95 ( m, 1H), 8.0 (d, 2H J= 6), 9.05 (d, 2H J= 6).
Preparation of 1-Aryl-piperidine2,4-diones Scheme R CO2Et Q¨N H2 N
R1 ______________________________________ Q. 7c/R1 DOM
N
Et0H, c.HCI CO2Et NEt3 CO2Et 0' \
or neat CO2Et Na0Et reflux Et0H
Q,N,,c/R1 MeCN, H20 oo 0 CO2Et Example 18 Preparation of Ethyl 3-(3-Chlorophenylamino)propionate 3-Chloroaniline (3.8g, 0.03 moles) was dissolved in ethanol (5m1) and ethyl acrylate (3.3g. 0.033moles) was added in ethanol (5m1). Concentrated hydrochloric acid (1m.1) was added and the reaction mixture was heated at reflux for 48 hours. Evaporated to a low bulk and dissolved the residue in dichloromethane and water. Basified to pH 9 with aqueous ammonia and separated. Evaporated off the dichloromethane under reduced pressure to give the crude product as a yellow oil (5.4g) Purified using a silica column eluted with isohexane:ethyl acetate 9:1 to give the required product (3.5g, 51%) as a colourless oil.
1H NMR CDCl3 5 1.30 (t, 3H, J = 6.5Hz), 2.65 (t, 2H, J = 6Hz), 3.45 (q, 2H J =

6Hz), 4.20 (q, 2H, J = 6.5Hz), 6.50 (m, 1H), 6.60 (m, 1H), 6.70 (m, 1H), 7.10 (m, 1H) Example 19 Preparation of N-(3-Chloropheny1)-N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester Ethyl 3-(3-Chlorophenylamino)propionate (3.5g, 0.0154moles) was dissolved in dichloromethane (40m1) and ethyl malonyl chloride (2.55g, 0.017moles) was added dropwise in dichloromethane (10m1) with stirring and cooling in order to keep the reaction temperature below 20 . Triethylamine (1.72g, 0.017moles) was added dropwise in dichloromethane (10m1). The reaction temperature was kept below 20 by ice bath cooling. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Washed with 2M hydrochloric acid, water and sodium bicarbonate solution. Dried over anhydrous magnesium sulphate, filtered and evaporated to give the required product as an orange oil. (4.5g, 86%) IHNMR CDCI3 8 1.25 (m, 6H), 2.65 (t, 2H, I = 7Hz), 3.20 (s. 2H), 4.10 (m, 4H), 7.15 (m, 1H), 7.30 (m, 1H), 7.40 (m, 2H) Example 20 Preparation of Ethyl 1-(3-chlorophenyl)piperidine-2,4-dione earboxylate Sodium (0.7g, 0.029moles) was dissolved in ethanol (90m1) and N-(3-Chloropheny1)-N-(2-ethoxycarbonyl-ethyp-malonamic acid ethyl ester (4.5g, 0.0132moles) was added in ethanol (30m1). The reaction mixture was heated at reflux overnight. The ethanol was evaporated off and the residue dissolved in water. Washed with diethyl ether and acidified to pH2 with concentrated sulphuric acid Extracted with dichloromethane and the combined dichloromethane extracts were combined. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give the product as an orange oil (2.8g, 72%) NMR CDCI3 8 1.40 (t, 3H, J = 5Hz), 2.85 (t, 21-1,1 = 6Hz), 3.85 (t. 2H J =
6Hz), 4.40 (q, 2H, J 5Hz), 7.20 (m, 2H), 7.30 (m, 1H), 7.35 (m, 1H) Example 21 Preparation of 1-(3-Chlorophenyl)piperidine-2,4-dione Ethyl 1-(3-chlorophenyl)piperidine-2,4-dione carboxylate (2.8g, 0.0095moles) was dissolved in acetonitrile (100m1)/water (10m1) and refluxed for 2 hours.
Evaporated to a low bulk and dissolved in dichloromethane. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give the product as an orange oil (2.2g). Purified using a silica column eluted with dichloromethane:ethyl acetate 9:1 to give the required product as a pale yellow gum (1.2g, 59%) 1H NMR CDC13 8 2.80 (t, 2H, J = 6Hz), 3.55 (s, 2H), 4.05 (t, 2H, .1 = 6Hz), 7.20 (m, 1H), 7.30 (m, 1H), 7.35 (m, IH), 7.40 (m, 1H) Also prepared in a similar manner were 1-Phenylpiperidine-2,4-clione 1H NMR CDC13, ppm) 8 2.80 (t, 2H, J = 6Hz), 3.6 (s, 2H), 4.05 (t, 2H, .1=
6Hz), 7.30 (m, 3H), 7.45 (m, 2H) 1-(3-Methylphenyl)piperidine-2,4-dione 1H NMR (CDC13, ppm) 8 2.40 (s, 3H), 2.80(t, 2H, 3= 6.5Hz), 3.6 (s, 2H), 4.05 (t, 2H, J = 6.5Hz), 7.30 (m, 3H), 7.45 (m, 2H) 1-(4-FluorophenyOpiperidine-2,4-dione NMR CDC13, ppm) 8 2.80 (t, 2H, J = 6Hz), 3.55 (s, 2H), 4.0 (t, 2H, J =
6Hz), 7.1 (m, 2H), 7.25 (m, 2H) 1-(3,5-Difluorophenyl)piperidine-2,4-dione 1-14 NMR (CDC13, ppm) 8 2.80 (t, 2H, J = 6Hz), 3.58 (s, 2H), 4.04 (t, 2H, J =
6Hz), 6.68-6.83 (m., 1H), 6.84-6.99 (m, 2H).
1-(3,5-Dichlorophenyl)piperidine-2,4-clione 1H NMR (CDC13, ppm) 5 2.80 (t, 2H, J = 6Hz), 3.58 (s, 2H), 4.02 (t. 2H, 3=
6Hz), 7.20-7.36 (m, 3H).
1-(4-Methylpyrid-2-yl)piperidine-2,4-dione NMR (CDC13, ppm) 5 2.41 (s, 3H), 2.75 (t, 2H, J = 6Hz), 3.62 (s, 2H), 4.44 (t, 2H, J = 6Hz), 6.94-7.02 (m, 1H), 7.72-7.79 (in, 1H), 8.25-8.36 (m, 1H).

Preparation of Cyc1ohexane-1,3-diones Scheme 2Et R5 401 R3 R5 R7 Na0Et R6 Example 22 Preparation of 4-( 4-Fluorophenyl )cyclohexane-1,3-dione Sodium ( 0.3g, 0.013moles ) was dissolved in ethanol ( 50ml ) and 4-Fluorophenylacetone ( 2.0g, 0.013moles ) was added in ethanol ( 10m1 ). Ethyl acrylate ( I.3g, 0.013 moles ) was and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and evaporated wider reduced pressure to give a brown gum. Dissolved in water and washed with diethyl ether. The aqueous layer was acidified to pH2 with conc. Hydrochloric acid and extracted with dichloromethane. The extracts were combined and washed with water. Dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to give an orange oil.. ( 1.7g ) This was purified using a silica column eluted with dichloromethane:ethyl acetate 8:2 and then dichloromethane:ethyl acetate 2:1 to give a colorless gum. (0.428g) This was triturated with diethyl ether/isohexane to give 4-(4-Fluorophenyl)cyclohexane-1,3-dione (0.28g) as a white solid.
IH NMR (CD30D, ppm) 8 2.1 (m, 1H), 2.3 (m, 1H), 2.4 (m, 2H), 3.7 (m, 1H), 4.9 (s, 2H), 7.1 (m, 2H), 7.2 (m, 2H).

Also prepared in a similar manner 4-Phenylcydohexane-1,3-dione 'H NMR (CD30D. ppm) 8 2.15 (m, 1H), 2.3 (m, 3H), 3.7 (m, 1H), 4.9 (s, 2H), 7.2 (in, 3H), 7.3 (in, 2H).

Preparation of Pyridazin-3-ones Scheme NaNO HCI z, ,NõCO2Me z¨NR2 ________ NI -N
DCB

NaOH
z ,N microwave z ,N, ,CO,H

Example 23 3-0xo-2-phenylhydrazono)pentanedioic acid dimethylester To a mixture of aniline (1.86g, 20mmol) in concentrated hydrochloric acid (10m1) and water (20m1) at a temperature below 5 C was added a solution of sodium nitrite (1.38g, 20mmol) in water (15m1) drop wise. The resultant mixture was stirred for 15 minutes and then it was poured into a solution of dimethylacetonedicarboxylate (3.48g, 20mmol) and sodium acetate (12g, 0.146mol) in ethanol (12m1) and water (40m1) causing an immediate precipitation. The suspension was stirred for 1 hour and then extracted with ethyl acetate (3 x 125m1). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 3-oxo-2-phenylhydrazono)pentanedioic acid dimethyl ester as a red oil (5.58g, quantitative) consisting of a mixture of E and Z isomers about the hydrazone NMR CDCI3 8 fi (singlets, 8H), 7.1-7.5 (m, 5H), 12.8 (s, 1H).
Example 24 Methyl 4-hydroxy-6-oxo-1 -phenyl-1,6-dihydropyridaaine-3-carboxylate 3-0xo-2-phenylhydrazono)pentanedioic acid dimethyl ester (12.5mmol) was dissolved in dichlorobenzene and heated at reflux for 24 hours and then allowed to cool to room temperature. The solvent was evaporated and the residue triturated with ether to give methyl 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylate a beige solid (2.4g, 78%) 1F1 NMR CDC13 8 4.0 (s, 3H), 6.4 (s, 1H), 7.4-7.6 (in, 5H), 10.3 (s, 1H).
Example 25 4-11ydroxy-6-oxo-1-pheny1-1,6-dihydropyridazine-3-carboxylic acid Methyl 4-hydroxy-6-oxo- 1 -phenyl- 1,6-dihydropyriclazine-3 -carboxylate (0.8g, 3.24mmol) was suspended in sodium hydroxide solution (20m1 of 2.0M) and heated at reflux for 1 hour. The mixture was allowed to cool to room temperature, acidified with 2M hydrochloric acid and extracted with ethyl acetate (3 x 15m1). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 4-hydroxy-6-oxo-l-pheny1-1,6-dihydropyridazine-3-carboxylic acid as a yellow solid (0.6g, 80%) 1H NMR CDC13 8 6.3 (s, IH), 7.35-7.7 (m, 5H).

Example 26 5-Hydroxy-2-phenyl-2H-pyridazin-3-one 4-Hydro x y-6-o xo-l-pheny1-1, 6-dihy dropyridazine -3-carboxylic acid (400mg, 1.72mmol) was heated at 270 C in a microwave for 3 minutes. The resultant black mixture was extracted into saturated sodium bicarbonate (I 5m1). The sodium bicarbonate solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 15m1). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to a crude solid (300mg). This was purified on a lOg SPE cartridge eluting with dichloromethane/ ethyl acetate (80:20 to 60:40) to yield 5-hydroxy-2-pheny1-2H-pyridazin-3-one (60mg) as a beige solid NMR D6 DMSO 8 6.05 (d, 1H, J = 2.7 Hz), 7.4-7.6 (m, 5H), 7.85 (d, 1H, J
= 2.7 Hz), 11.6(s, IH).
The following compounds are also active in the method of the present invention:
2-( 4-Chlorophenyl )-5-hydroxy-2H-pyridazin-3-one 5-Hydroxy-24 3-trifluoromethylphenyl )-2H-pyridazin-3-one The following synthesis is described in J. Het Chem. 1989, 26, 169-176 Scheme 1) YCHOQõN KOH QõN
N N
Q¨NHNH2 2 ) Et0H 0 y Et0H
water 0 OH
2) Acetic acid Y = Cl, Br 1 0%Pd/C 1MNaOH
H2 Et0H
QõN
N

Example 27 2-(3,5-DifluarophenyI)-5-hydroxypyridazin-3-one 4-Bromo-2-(3,5-difluoropheny1)-5-hydroxypyridazin-3-one (0.6g, 1.98mmoles) was dissolved in ethanol (50m1) and 1M sodium hydroxide (4m1) was added_ 10% Palladium on carbon (0.15g) was added and the flask was placed under an atmosphere of hydrogen (balloon) with stirring. The reaction mixture was stirred overnight at room temperature. Filtered off the catalyst using Hyflo and evaporated to dryness. Added 2M hydrochloric acid and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate.
Filtered and evaporated the filtrate to give a white solid. Triturated with diethyl ether to give the product as a white solid. (0.32g, 72%) 1H NMR DMS0d6 612.2 ( br s, 1H), 7.9 (d, 111, J = 3Hz), 7.3 (m., 5H), 6.1 (d, 1H. J = 3Hz) Also prepared in a similar manner 2-(2,5-Difluoropheny1)-5-hydroxypyridazin-3-one 1H NMR DMS0d6 611.8 (br s, 1H), 7.85 (d, 111, J = 2.5Hz), 7.4 (m, 411), (d, 1H, J = 2.5Hz) Example 28 4-Bromo-2-(3,5-difluorophenyI)-5-hydroxypyridazin-3-one 4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one (1.5g, 0.0041moles) was suspended in ethanol (50m1) and potassium hydroxide (0.8g, 0.0123moles) was added in water (8m1). Refluxed for 4 hours with stirring. Evaporated to a low bulk and diluted with water. Acidified to p112 with conc. hydrochloric acid and extracted with ethyl acetate. Washed with water and dried with anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give an orange solid.
Triturated with diethyl ether and dried in a desiccator to give the product as a cream solid. (0.7g, 56%) 1H NMR DMS0d6 612.5 (br s, 1H), 7.9 (s, 1H), 7.35 (m, 3H) ; 19F NMR 5 110 Also prepared in a similar manner 4-Bromo-2-(2,5-difluoropheny1)-5-hydroxypyridazin-3-one NMR DMS0d6 67.9 (s, 1H), 7.5 (m, 3H) ; 19F NMR 6117, 126 4-Bromo-2-(2,5-dichlorophenyI)-5-hydrorypyridazin-3-one NlvfR DMS0d6 8 7.9 (s, 1H), 7.8 (d, 1H, J = 2.5Hz), 7.7 (d, 1H, 3= 8.5Hz), 7.6 ( d,d, 1H, 3 = 2.5, 8.5Hz) Example 29 4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one Mucobrornic acid (2.8g, 0.011moles) was dissolved in ethanol (75m1) and 3,5-di-Fluorophenyl hydrazine hydrochloride (1.8g. 0.01moles) was added. After 30 minutes, triethylamine (1,4m1, 0.01moles) was added. The reaction mixture was stirred at room temperature for 3 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (80ral). Refluxed with stirring overnight to give a brown solution. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (3.4g, 93%) 1H NMR DMS0d6 68.3 (s, 1H), 7.4 (m. 3H); 19F NMR 8 109 Also prepared in a similar manner 4,5-Dibromo-2-(2,5-dichlorophenyl)pyridazin-3-one 1H NMR DMS0d6 8 7.9 (s, 1H), 7.45 (m, 1H), 7.4 (m, 2H) 4,5-Dibromo-2-(3,5-dichlorophenyl)pyridazin-3-one 1H NMR DMS0d6 68.35 (s, 1H), 7.8 (m, 1H), 7.7(m,2H) 4,5-Dibrome-2-(2,5-difluorophenyppyridazin-3-one NMR DMS0d6 ö 8.35 (s, 1H), 7.5 (m, 3H) Scheme QNõN 1 ) nBuLi N Na0Me THF N
o/Br MeON (:)(:3 2) Br Br KOH
Et0H
H20 y QõN
N
0' OH
Example 30 2(3,5-Dichloropheny1)-5-hydrorypyridazin-3-one 2-(3,5-DichlorophenyI)-5-methoxypyridazin-3-one (0.25g, 0.92mmoles) was suspended in ethanol (40m1) and potassium hydroxide (0.12g, 1.8mmoles) was added in water (5m1). Refluxed overnight with stirring to give a yellow solution.
Evaporated to dryness and added 2M hydrochloric acid. Extracted with ethyl acetate (x2) and washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give a yellow solid. Triturated with dichloromethane to give a pale yellow solid. (0.1g, 42%) 1H NMR DMS0d6 8 7.75 (d, 1H. J = 3Hz), 7.6 (m, 2H), 7.5 (m, 1H), 6.25 (d, 1H, J = 3Hz) Also prepared in a similar manner 2-(2,5-Dichloropheny1)-5-hydroxypyridazin-3-one 1H NMR DMS0d6 610.9 (br s, 1H), 7.7 (d, 1H, J 3Hz), 7.4 (rn, 1H), 7.35 (m, 11-1), 7.3 (m, 1H), 6.2 (d, 1H, J = 3Hz) Example 31 2-(3,5-Dichloropheny1)-5-methoxypyridazin-3-one 4-Bromo-2-(3,5-dichloropheny1)-5-methoxypyridazin-3-one (2.5g,0.0071moles) was dissolved in THF (250m1) and cooled to ¨50 under nitrogen. 1.6M n-Butyl lithium (6.7m1, 0.011moles) was added dropvkise with stirring. Allowed to warm to ¨200 over 1 hour. Added 1 equivalent of 1.6M n-Butyl lithium (4.4m1, 0.0071moles) dropwise. Stirred at ¨20 for 30minutes. Poured into ammonium chloride solution and stirred for 15minutes. Extracted with Et0Ac (x2) and washed with water. Dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown solid. (3.0g) Purified using MPLC ( silica, eluted with dichloromethane: Et0Ac 9:1) to give a yellow solid. (0.25g, 13%) Not pure used directly in the next reaction.
1H NMR DMS0d6 67.7 (d, 1H, J = 3Hz), 7.6 (d, 2H, J= 2Hz), 7.5 (d, 1H, J =
2Hz), 6.2 (d, 1H, J = 3Hz) Also prepared in a similar manner 2-(2,5-Dichloropheny1)-5-methoxypyridazin-3-one 1H NMR DMS0d6 5 7.95 (d, IR, J = 3Hz), 7.75 (d, 1H, J = 2.5Hz), 7.7 (d, 1H, J = 8Hz), 7.6 (d, d, IH, J = 2.5, 8Hz), 6.45 (d, 1H, J = 3Hz) Example 32 4-Bromo-2-(3,5-dichloropheny1)-5-methorypyridazin-3-one Sodium (0.28g, 0.012moles) was dissolved in methanol (100m1) and a suspension of 4,5-Dibromo-2-(3,5-dichlorophenyl)pyridazin-3-one ( 4.0g, 0.01moles) in methanol (60m1) was added. Refluxed overnight. Evaporated to dryness and added water. Filtered off the solid and dried in a dessicator.
Triturated with ether and dried in a dessicator. (3.1g, 89%) 1H NMR DMS0d6 8 8.35 (s, 1H), 7.75 (m, IH), 7.7 (m, 2H), 4.15 (s, 3H) Also prepared in a similar manner 4-Bromo-2-(2,5-dichlorophenyI)-5-methaxypyridazin-3-one 1H NMR DMS0d6 8 8.35 (s, 1H), 7.8 (d, 1H, J = 2.5Hz), 7.7 ( d, 1H, .1" =
8.5Hz), 7.65 (d of d, 1H, J = 2.5, 8Hz), 4.15 (s, 3H) Scheme CICO21'i 1) QõN KOH QõN
CI CHO N N
Q¨NHNH2 ____________ Et0H water 2) Acetic acid CI CI
Example 33 4-Chloro-2-phenyl-5-hydroxypyridazin-3-one 4,5-Dichloro-2-phenylpyridazin-3-one (2.4g, 0.01moles) was suspended in ethanol (50m1) and potassium hydroxide (2.0g, 0.03moles) was added in water (20m1). Refluxed for 4 hours. Evaporated to dryness and added water. Acidified to pH2 with c. hydrochloric acid. Filtered off the product as a buff solid and dried in a desiccator. (2.1g) Took 0.5g and dissolved in methanol, filtered and evaporated. Triturated with ether to give the product as a cream solid. ( 0.4g, 76%) 11-11\TMR DMS0d6 5 7.9, (s, 1H), 7.5 (m, 4H), 7.4 (m, 1H) Example 34 4,5-Dichloro-2-phenylpyridazin-3-one Mucochloric acid (9.3g, 0.055moles) was dissolved in ethanol (60m1) and phenyl hydrazine (5.4g, 0.05moles) was added. The reaction mixture was stirred at room temperature for 2 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (60m1). Refluxed with stirring for 3hours.

Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (11.0g, 91%) IFINMR DMS0d6 8 7.95 (s, 1H), 7.5 (m, 4H), 7.4 (m, 1H) The following compounds have also been found to be effective in treating glaucoma or ocular hypertension according to the method of the present invention.
R

R = H; 2-CO2H, 5-CI
H Nishino et al. Tetrahedron, 2005, 11107-11124 H Nishiiao et al. Heterocyclic Comm. 2005, 11, 379-384 Bekhli et al. Chem. Heterocyclic Compds. Engl. Trans. 1970, 6, 814 Cyclohexane-1,3-diones R = H, 4-0Me See EP 291114 (R = H, 4-0Me), US 4546104, US
4795488 (R = 2-F) Bergmann et al. J. Am. Chem. Soc. 1953, 3226 R = 3,4-Di0Me See Synthesis 1980, 394-397 R =4-C1 See J. Med. Chem. 1981, 1006-1010 Pyridazin-3-ones CI = 10 CI
,N, ,N
N
N

"
R2 Br Nissan, EP 210647 Pharmacia, W02005007632 R2 = H, CI
CI CI
=
NN
, ,t\1 N
OH CI
0" OH
R2 Br Nissan, EP 210647 Pharmacia, W02005007632 R2 = H, CI

R5 ei R3 ,N

i) R_,3, R4. R5, R6, R7 = H

ii) R3 = CF3, R4-R7 = H
R4 = CF3, R3, R.5-R7 = H
iv) R5 = Cl, R3, R4, R6, R7 = H
i) Maier et al. Hely. Chim. Acta. 1954, 37, 523 J. Het. Chem. 1989, 26, 169-176; J. Het. Chem. 1990, 27, 471-477 i) R3, R4, R5, R6, R7 = H
iii) R4 = CF3, R3, R.5-R7 = H
ii) R4 = CF3, R3, R5-R7 H; iv) R5 = Cl, R3, R4, R6, R7 = H
411:1 ,N
N

R2 = OMe Chem. Pharm. Bull. 1971, 1635 1972, 747 R2 = SEt Collect. Czech. Chem. Comm. 1980, 45, It is apparent to one of ordinary skill in the art that different pharmaceutical compositions may be prepared and used with substantially the same results. That is, other Abnormal Cannabidiols will effectively lower intraocular pressure in animals and are within the scope of the present invention.
Also, the novel compounds of the present invention may be used in a method of providing neuroprotection to the eye of a mammal in a similar manner to the abnormal Cannabidiols of Published U.S. Patent Application 2005/0282912.

Claims (13)

1. A compound of formula I useful for treating glaucoma or ocular hypertension wherein Y is selected from the group consisting of O and OH;
Z is N or C;
Q is wherein W is a direct bond or C(R11)(R12); a dotted line represents the presence or absence of a double bond; the wavy line represents a direct bond;
R is selected from the group consisting of H, halogen and C1-5 alkyl;
R1 is selected from the group consisting of H and halogen;
R2 is independently selected from the group consisting of H, C1-5 alkyl, halogen, XC 1-5 alkyl, C
1-5 alkylOR13, C1-5 alkylN( R13 )2, N( R13 )2, XC1-5 alkylN( R13)2 and XC1-5 alkylOR13;
X is O or S(O)n;
n is 0 or an integer of from 1 to 2;
R3 is selected from the group consisting of H, hydroxyl C1-5 alkyl, C1-5 alkylOR13 and C1-5 alkylN( R13 )2;

R4 is selected from the group consisting of H, C1-5 alkenyl, C2-5 alkyl, C1-5 alkylOR13 and C1-5 alkylN( R13 )2;
R5, R6, R7, R8, R9, R10, R11, R12 are independently selected from the group consisting of H, C1-5 alkyl, C1-5 alkylOR13 and OR13; and R13 is selected from the group consisting of H, C1-5 alkyl and C3-8 cyclic alkyl, or two R13 groups, together with N or O, may form a cyclic ring such as a piperidine or morpholine ring; and provided that any of said alkyl groups may be substituted with a hetero atom containing radical, wherein said heteroatom is selected from the group consisting of halogen, oxygen, nitrogen and sulfur, R8 and R12 may, together, form a cyclic ring, and R3 and R5 may, together, represent O, and when Q is menthadiene, R1 and R2 are H and Y is hydroxyl, R may not be H or alkyl.
2. The compound of Claim 1 wherein said compound is a compound of formula II
3. The compound of claim 2 wherein R is selected from the group consisting of hydrogen, methyl, bromo and ethyl and R2 is selected from the group consisting of hydrogen, methyl and chloro.
4. The compound of claim 1 wherein said compound is a compound of formula III
5. The compound of claim 1 wherein said compound is a compound of formula IV

6. The compound of claim 2 wherein R is selected from the group consisting of hydrogen, methyl, bromo and chloro; R1 is selected from the group consisting of hydrogen, methyl and chloro, R2 is hydrogen, R3 is methyl, R5 R6, R7, R8, R9, R10, R11 and R12 are hydrogen and R
is isopropenyl.
7. The compound of claim 1 wherein said compound is 4-(1-isopropyl-4-methyl-1,2,5,6-tetra-hydropyridin-2-yl)-5-methylbenzene-1,3-diol.
8. A pharmaceutical composition which is an ophthalmic solution comprising the compound according to any one of claims 1-7 and an opthalmically acceptable liquid.
9. A pharmaceutical product, comprising a container adapted to dispense its contents in metered form, and the composition as defined in claim 8.
10. Use of the compound according to any one of claims 1 to 7 for topical administration to the eye for treating glaucoma or ocular hypertension.
11. Use of the compound according to any one of claims 1 to 7 for the production of a medicament for topical administration to the eye for treating glaucoma or ocular hypertension.
12. Use of the compound according to any one of claims 1 to 7 for topical administration to the eye for treating glaucoma or ocular hypertension, wherein said use is in combination with a second drug selected from the group consisting of 13-blockers, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, chlolinesterase inhibitors, glutamate antagonists, prostamides and prostaglandins.
13. Use of the compound according to any one of claims 1 to 7 for the production of a medicament for topical administration to the eye for treating glaucoma or ocular hypertension, wherein said use is in combination with a second drug selected from the group consisting of 13-blockers, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, chlolinesterase inhibitors, glutamate antagonists, prostamides and prostaglandins.
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US11/409,570 US7612101B2 (en) 2006-04-24 2006-04-24 Abnormal cannabidiols as agents for lowering intraocular pressure
US11/409,868 US7718830B2 (en) 2006-04-24 2006-04-24 Abnormal cannabidiols as agents for lowering intraocular pressure
US11/409,570 2006-04-24
US11/409,868 2006-04-24
US11/409,871 2006-04-24
US11/409,871 US7618966B2 (en) 2006-04-24 2006-04-24 Abnormal Cannabidiols as agents for lowering intraocular pressure
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JP2014058536A (en) 2014-04-03
WO2007127711A2 (en) 2007-11-08
CA2648884A1 (en) 2007-11-08
US7968711B2 (en) 2011-06-28
BRPI0710732A2 (en) 2011-11-08
WO2007127711A3 (en) 2008-03-27
AU2007244978B2 (en) 2013-05-30
EP2123264A1 (en) 2009-11-25
CA2648884C (en) 2015-10-13
US20110269715A1 (en) 2011-11-03
US20070249596A1 (en) 2007-10-25
EP2010165A2 (en) 2009-01-07
AU2007244978A1 (en) 2007-11-08
JP2009536623A (en) 2009-10-15

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